Hepatocyte Growth Factor (HGF), also known as Scatter Factor (SF), is a multi-functional heterodimeric protein produced predominantly by mesenchymal cells and is an effector of cells expressing the Met tyrosine kinase receptor (“c-Met”)(Bottaro et al. (1991) SCIENCE 251: 802-804, Rubin et al. (1993) BIOCHIM. BIOPHYS. ACTA 1155: 357-371). Mature HGF contains two polypeptide chains, the α-chain and the β-chain. Published studies suggest it is the α-chain that contains HGF's c-Met receptor binding domain.
Mature HGF contains two polypeptide chains, the α-chain and the β-chain. Upon binding to its cognate receptor, HGF mediates a number of cellular activities. The HGF-Met signaling pathway plays a role in liver regeneration, wound healing, neural regeneration, angiogenesis and malignancies. See, e.g., Cao et al. (2001) PROC. NATL. ACAD. SCI. USA 98: 7443-7448, Burgess et al. (2006) CANCER RES. 66: 1721-1729, and U.S. Pat. Nos. 5,997,868 and 5,707,624.
Dysregulation of cell signaling pathways that mediate proliferation, survival, and migration are an underlying cause of many cancers. In particular, dysregulation and over-expression of the Met tyrosine kinase receptor correlates to poor prognosis in many human tumors, making it an attractive target for therapeutic intervention.
There are currently no FDA approved therapeutics targeting the Met receptor, however, a few candidate molecules are in various stages of clinical trials. As such, molecules that potently inhibit Met receptor activation may have a significant impact on cancer therapy. In addition, studies to develop Met-targeted molecular imaging agents for non-invasive visualization of Met expression in vivo have been extremely limited compared to other cancer targets. The availability of such imaging agents would aid in cancer diagnosis, staging, and disease management, as well as help identify patients who would be good candidates for Met-targeted therapies.
The present invention provides potent activators and inhibitors of the Met receptor, methods for their production and use.